All adults with Down syndrome (DS) over 40 years of age exhibit Alzheimer's disease (AD) neuropathologically, due in part to the overexpression of the amyloid precursor protein gene within the obligate DS region on chromosome 21. While the onset of AD was once considered an inexorable result of growing old with DS, a number of studies have clearly established that although adults with DS over the age of 50 are at substantial risk for the development of AD, risk does not appear to reach 100%. Substantial individual differences are evident within this population, suggesting that there should be biological factors that contribute to this heterogeneity. However, with the exception of age, apolipoprotein E (APOE) genotype, age at menopause and cholesterol level, few additional risk factors have been identified. The overall aim of this study is to determine if a continuum of symptoms, including adiposity, glucose metabolism irregularities, dyslipidemia, and hypertension, influence cognitive decline and risk for AD in adults with DS. Adiposity leads to insulin resistance, which leads to hyperinsulinemia, which leads to glucose intolerance and/or diabetes, hypertension, dyslipidemia, and inflammation. This confluence of conditions has been referred to as the Metabolic syndrome. The key component of the Metabolic syndrome is high insulin levels (hyperinsulinemia). Hyperinsulinemia, as well as components of the Metabolic syndrome, in combination and individually, have been reported to be related to increased risk for AD in persons without DS. The guiding hypothesis of this subproject is that features of the Metabolic syndrome, and particularly insulin resistance/hyperinsulinemia, is related to an increase in cognitive decline and AD onset in DS, as has been observed in persons without DS. A secondary aim is to determine whether the use of secondgeneration antipsychotics or statins may influence the risk for cognitive decline and onset of AD as a function of their physiological action upon the Metabolic syndrome. Insulin resistance/hyperinsulinemia and other aspects of the Metabolic syndrome can be remediated through even modest weight loss, exercise and pharmaceutical intervention. Results from this study may suggest possible targets for subsequent clinical intervention leading to delay or reduction of AD incidence in persons with DS. Clinical trials to treat hyperinsulinemia in persons with AD without DS are already in phase III.